Drexel University

NIH Research Projects · FY 2026 · 2025-01

Parent-mediated early interventions for autism during toddlerhood are beneficial; however, intensive, autism- specific interventions typically do not begin until a child receives a diagnosis. As the median age of diagnosis in the US is 49 months, and services often do not begin for another 9 months post-diagnosis on average, this creates harmful delays. Such delays in accessing autism-specific early interventions are potentially avoidable, as caregivers of children later diagnosed with autism often identify concerns about their child’s development by 13 months on average– including difficulties that can be successfully addressed through evidence-based intervention practices. Wait times to receive a formal diagnosis of autism are such a significant barrier that they have been referred to as a “crisis” in the field, with parents reporting an average wait time of 1.2 years in the US and even longer in Canada. The current proposal focuses on circumventing the roadblock of delayed access to diagnosis and intervention by empowering caregivers to address their children’s needs before a diagnosis is established. This will be accomplished through the implementation and evaluation of the “Online Parent Training in Early Behavioral Intervention (OPT-In-Early)”, an online resource for caregivers of autistic children which will be made available to caregivers who are awaiting a diagnostic evaluation for their child. The Opt-In-Early program includes modules designed for self-directed implementation and individualization based on caregiver priorities, as well as access to remote consultation with a clinician for advice, clarification and support. Following an alternative approach to the current “parental concerns – then enrolment in waitlist – then clinical diagnosis – then intervention”, the proposed program is designed to counteract the harmful and frustrating inaction that characterizes the waiting period with timely action designed to address areas of concerns that caregivers have already identified and should be empowered to address. The evaluation of this innovative program will be achieved by comparing outcomes for 120 children aged 16-48 months who are on a waitlist to receive a formal autism diagnosis, randomly assigned to receive either OPT-In-Early or to a waitlist condition for 6 months. Examining whether accessing and using OPT-In-Early during waitlist time is a viable alternative to the current “first diagnosis then intervention” format can be a critical step toward promoting a more efficient intervention delivery model, bridging the gap between timing of parental concerns and availability of interventions designed to target such concerns. Therefore, in the context of the current waitlist crisis and chronic shortage of trained professionals in the areas of autism diagnosis and intervention, the proposed project has the potential for a high impact in the field. Additionally, given the alignment of OPT-In-Early with other evidence-based interventions, the relevance of this research question extends beyond the intervention under examination.

NIH Research Projects · FY 2026 · 2024-12

ABSTRACT It has been recently hypothesized that it is the persistent expression of certain transcription factors (TFs), called ‘terminal selectors’ that specify a neuron’s identity. Terminal selectors are thought to be expressed throughout development and adulthood, and determine a cell’s terminal characteristics, such as morphology, gene expression, and connectivity. However, in the majority of cell populations, the identities of terminal selectors, the characteristics they control, and the mechanisms by which they control each characteristic are still largely unknown. This proposal aims to establish mechanisms by which terminal selectors determine identity during development by using the well-studied model organism Drosophila melanogaster. Utilizing a single-cell RNA sequencing (scRNA-seq) transcriptional atlas of the fly visual system and knockdown/overexpression experiments, we identified a novel terminal selector, broad, which seemingly differentiates identity between two closely related visual projection neuron cell types. The terminal characteristics that differentiate these two cell types, including connectivity and function, are well established, and their experimental accessibility makes them an ideal model to study principles of terminal identity. We hypothesize that broad acts as a terminal selector between two cell types, acting to determine morphology, gene expression, and connectivity between two genetically similar cell types. To evaluate our hypothesis, in Aim 1 we first establish TFs that act as terminal selectors by (1) using knock-down and overexpression constructs to determine impacts on morphology, (2) utilizing scRNA-seq to determine impacts on gene expression and (3) performing whole-cell electrophysiology after hypothesized presynaptic inputs have changed to determine impacts on connectivity. In Aim 2 we will identify mechanisms underlying the changes in wiring patterns following terminal selector perturbations, utilizing (1) scRNA-seq, (2) DNA adenine methyltransferase identification (DamID) sequencing, and (3) knock- down/overexpression experiments. This fundamental research will expand the scientific community’s understanding of how neuronal identity arises and the minimal requirements for establishing identity characteristics. This work will also provide insight on how failures to appropriately specify neuronal cell types can contribute to neurodevelopmental and neuropsychiatric disorders.

NIH Research Projects · FY 2026 · 2024-12

Abstract A critical function performed by visual systems is the fast and reliable detection of features within the environment, such as moving objects or approaching threats. Neurons predicted to encode these higher order, behaviorally relevant visual features have been identified in a variety of species. However, a lack of cell-type specific genetic tools, accessible neural anatomy, and clearly mapped neural circuitry has limited the identification of these cell-types, and led to an incomplete understanding of the mechanisms which govern feature encoding in visual systems. Here, we investigate visual feature encoding by leveraging Drosophila melanogaster. We specifically investigate mechanisms governing visual feature encoding in visual projection neurons (VPNs), a class of neurons predicted to selectively encode visual features. We focus on two VPN populations, Lobula Plate/Lobula Columnar type 1 (LPLC1) and Lobula Plate/Lobula Columnar type 2 (LPLC2). Previous studies have suggested these two neuron types encode the visual features of an object approaching on a direct collision course, however their hypothesized selectivity to visual features and the origins of this selectivity have yet to be thoroughly investigated. Differences in recording location and stimulus parameters during Ca2+ imaging have made it difficult to resolve feature tuning across studies. Additionally, our preliminary data that demonstrate these neurons are spiking, contrary to prior assumptions, suggest feature selectivity may emerge from a spike timing code, which has to date been ignored. Thus, there is a critical need to study these neuron populations using whole-cell electrophysiology and precisely designed stimuli to understand the mechanisms governing their feature encoding and reveal their selectivity to specific visual features. The goal of this project is to uncover feature tuning for these neurons at the level of individual spikes and investigate the mechanisms governing their feature selectivity. To accomplish this goal, we will first map the receptive fields of LPLC1 and LPLC2 and characterize responses to an array of visual stimuli to establish their feature selectivity (Aim 1). Following this, we will investigate the mechanisms of inhibition that shape both the feature and receptive field selectivity (Aim 2). Finally, we will investigate how neuron active properties further govern feature selectivity within these neurons through multicompartment modelling (Aim 3). Findings from our work will reveal the specificity and underlying mechanisms for feature encoding within two VPN types, which may serve as a foundation for investigating feature detecting neurons in other, more complex species. Drosophila possess a visual system with striking similarities to vertebrate visual systems, so our findings may provide general principles for collision detection. In the longer term, a more fundamental understanding of visual feature encoding in fruit flies may help the development of human therapeutics for those suffering from blindness.

NSF Awards · FY 2024 · 2024-12

The broader impact/commercial potential of this I-Corps project is the development of an advanced tissue engineering product. Effective knee cartilage repair requires a blend of surgical precision and supportive biomaterials that foster cartilage regeneration. Existing solutions often face challenges like poor integration, inadequate cellular environments, and prolonged rehabilitation, leading to graft failures, reoperations, increased work absences, and high costs. The proposed technology addresses these issues with a phase-transformable scaffold composed of inter-crosslinkable, protein-based microribbons. These microribbons can solidify into a porous scaffold with optimal tissue-specific porosity. The injectable nature of our technology supports minimally invasive procedures, allowing it to conform to and fill defects of varying geometries before solidifying. This adaptability enhances implant integration with host cartilage. The tunable ribbon size optimizes pore structure for 3D cartilage growth. Preliminary in vitro and explant tests have shown advantages, and further evaluations using horse models are underway. This I-Corps project utilizes experiential learning coupled with a first-hand investigation of the industry ecosystem to assess the translation potential of the technology. This solution is based on the development of a new method to transform collagen, the key component of cartilage, into microscopic ribbons. During surgery, these ribbons can be crosslinked with blue light to create a tissue-engineering scaffold. Chondrocytes, the cells responsible for cartilage formation, are pre-mixed with the microribbons before crosslinking, forming a scaffold that encapsulates the cells. The technology functions on both microscopic and macroscopic levels. Microscopically, the microribbons, which are approximately 0.01 mm wide—about the size of chondrocytes—regulate cell shape and movement, activating cartilage-producing processes. On a macroscopic level, the paste-like microribbons, containing cells, can be injected into cartilage defects of any shape. Once injected, they are crosslinked into a solid scaffold that integrates with the existing cartilage, enhancing healing and repairing the defect. This innovative approach is designed to significantly improve cartilage repair and regeneration. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2024 · 2024-10

This project aims to serve the national interest by developing and providing novel social emotional learning (SEL) support and skill development for first-year undergraduate engineering students. COVID-related learning losses have exacerbated the existing structural inequities in K-12 education leaving a growing number of students ill-prepared for the rigors of university life. Included in these learning losses are the social-emotional skills required for college and career success in the 21st century. To support students as they develop these skills, the project team plans to integrate SEL interventions and structural changes into first-year mathematics and engineering courses and to analyze the efficacy of these efforts. Through the collaborative efforts of faculty from engineering and mathematics, this project will develop and assess remedial and preventative interventions that will directly impact 400 - 500 students/year. First, a novel remedial intervention in first-year math courses will encourage struggling students to reflect not just on technical content but also on the barriers they face, the personal support networks to which they have access, and the extent to which they utilize the academic supports available to them. Second, the project team intends to develop and assess preventative SEL interventions by modifying an existing 1-unit first-year seminar. Offering cohorts by major will introduce first-year students to peers, faculty, and upperclassmen for earlier, stronger engineering identity formation. Modifying the curriculum to include SEL instruction will encourage introspection and self-awareness. Third, the project team will complete qualitative research by analyzing student artifacts and conducting interviews with high-risk students who succeed despite low incoming math scores. Results will be assessed via quantitative comparison of grades and SEL instruments scores pre/post interventions, between test/control course sections, and against historical data. The results of this study will provide generalizable understanding of how first-year engineering students develop SEL skills and how they can be measured. Results will be disseminated internally and externally through peer-reviewed publications, professional societies, and personal networks. The NSF IUSE: EDU Program supports research and development projects to improve the effectiveness of STEM education for all students. Through the Engaged Student Learning track, the program supports the creation, exploration, and implementation of promising practices and tools. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2024 · 2024-10

The objective of this Civic Innovation Challenge (CIVIC) project is to support research on developing, piloting, and evaluating CORELADE, a novel home delivery model that COllects, RELAys, and DElivers surplus food to food-insecure aging communities through nonprofit organizations. By 2050, 20% (or 84 million) of the U.S. population will reach the age of 65. As the number of seniors grows, so does the need for food security. The number of food-insecure seniors rose from 4.9 million in 2016 to 5.2 million in 2020 and continues to grow. One solution is to provide home delivery through non-profit organizations. However, while commercial home delivery models have witnessed great success, they do not translate well to the nonprofit sector as volunteers typically find home delivery tasks — the time and costs involved — very demanding. Thus, there is an urgent need to make non-profit organizations’ home delivery models better aligned with capabilities and motivations of volunteer workforce, ensuring that the system is efficient, equitable, and financially sustainable. CORELADE aims to substantially increase seniors’ access to healthy food in the pilot communities, thus improving their quality of life and community wellbeing. CORELADE research will leverage complementary capabilities of nonprofit organizations’ vehicle fleets and volunteers' personal vehicles for food collection and delivery, with the intent of utilizing strategically located relay stations to reduce the logistical burdens. It draws on theories and methods from behavioral psychology, optimization and data analytics, computing, and community engagement to optimize food collection and delivery plans, thereby minimizing the efforts associated with home delivery. As a result, CORELADE hopes to motivate volunteers to take on home delivery tasks, extend the scope of non-profit home delivery initiatives, and ultimately create food-secure communities for senior population. This project involves academic researchers from Drexel University, Sharing Excess (a non-profit organization Based in Philadelphia, dedicated to ending food insecurity) and two organizations serving aging communities in the Philadelphia region (University Square Apartments and ElderNet). It is expected that CORELADE not only improves Sharing Excess’s operations but also serves as a scalable model for communities across the country. This project is in response to the Civic Innovation Challenge program’s Track B. Bridging the gap between essential resources and services & community needs and is a collaboration between NSF, the Department of Homeland Security, and the Department of Energy. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2024-09

This proposal seeks to develop a new imaging pipeline that will examine tissue level and nuclear level spatial architecture of histone dopaminylation in the CNS of ecoHIV infected mice allowed to self administer cocaine. To achieve this goal we will develop a new imaging pipeline that that collects large numbers of images (>15,000 per animal and brain region) and analyzes them using a novel AI-powered, machine learning approach. Substance use disorders (SUD) are a chronic disease of the CNS that are characterized by compulsive craving that persists even after substance use ceases. The development of SUD is associated with a transition in brain physiology that maintains drug seeking and taking. Epigenetics, the change in gene expression without change to DNA sequence, and the underlying mechanisms of histone modification, transcription factor recruitment and DNA packaging, is involved in an array of neurodegenerative diseases, including control of HIV transcription. Furthermore, there is evidence that substance use drives changes in chromatin structure and therefore may alter gene expression, and that these changes may play a role in relapse to drug use. Recent studies have shown that dopamine can modify histones of cells in the CNS and that dopaminylation drives cocaine seeking behavior in rodents. Techniques that can connect the available powerful single cell molecular approaches and gross examination of the CNS by both traditional histology and modern non-invasive imaging for the study of HIV and substance use have not been used extensively. We propose to address this technical shortcoming by combining our strengths in epigenetics, high resolution imaging of the CNS, computational biology and animal behavior. We will query sub-nuclear and tissue region architecture of epigenetic modifications, including the newly discovered dopaminylation of histone H3 (H3Q5dop), analyze the resulting data using a machine learning based pipeline, and then correlate this architecture to behavioral outcomes as they relate to drug seeking behavior. In addition to the creation and testing of new technologies, we will address the hypothesis that altered dopaminylation of histones in astrocytes is the mechanism by which HIV infection enhances sensitivity to cocaine’s neurobehavioral properties. We develop our technology in the R61 exploratory phase (Aim 1: Imaging of H3Q5dop and other epigenetic marks in nuclei isolated from mice self-administering cocaine, Aim 2: Assess applicability of tissue clearing protocols to whole-tissue imaging of histone modification, Aim 3: Determine applicability of NUCLEO-M and tissue clearing microscopy to existing tissue bank samples) and fully test our behavioral hypothesis in the R33 application phase (Aim 4: Assess the independent and interactive effects of cocaine exposure on nuclear architecture in a model of HIV infection, Aim 5: Determine the contribution of dopaminylation to the regulation of cocaine seeking in a mouse model of HIV infection)

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY/ABSTRACT Climate change-related extreme weather – extreme heat, heatwaves, and intense rainfall – pose an urgent threat to public health. Children may bear a disproportionate burden of the adverse effects of extreme weather for a multitude of reasons, including their immature and developing bodies, low body mass, and dependence on caregivers to respond to environmental threats. A growing body of literature, including studies from our own research group, shows links between extreme weather and acute childhood morbidity. Nevertheless, there remain critical knowledge gaps, including incomplete characterization of the scope of pediatric health outcomes related to weather extremes and almost no assessment of chronic health (lasting) impacts. We propose to conduct a large, multi-site study of the relationship between extreme weather and children’s health by linking data from PEDSnet – a research consortium of U.S. pediatric health systems, including over 12 million children, spanning the years 2009 through 2023 – with high-resolution geospatial measures of extreme weather and residential neighborhood environments. Specifically, we aim to: 1) Estimate associations of extreme weather events – hot temperatures, heatwaves, heavy rainfall, and intense rainstorms – with a broad scope of acute adverse health events in children, such as dehydration, asthma exacerbation, respiratory infections, acute gastroenteritis, injuries, and acute care for mental health disorders; 2) Investigate the relationship between cumulative exposure to multiple, possibly repeated extreme weather events, and development of chronic health conditions during childhood – including mental health disorders, asthma and allergic rhinitis, and overweight/obesity – assessing initial development of the condition, as well as its persistence; 3) Quantify disproportionate impacts of extreme weather on children according to small-area (census-tract) indicators of residential neighborhood-level social and infrastructural vulnerability. Our study will considerably advance scientific understanding of relationships between climate-change related weather extremes and children’s health. Given the geographical diversity of the study area, the size of the patient population included, the detailed richness of our compiled database, and the novel investigation of chronic health outcomes, this project will have a sustained impact on the state of knowledge about the scope, magnitude, and inequities of children’s health outcomes from extreme weather.

NIH Research Projects · FY 2024 · 2024-09

Project Summary Drexel University is a prestigious, highly diverse R1-level institution built upon a strong history of interdisciplinary collaborations across its many departments and campuses. Drexel University recognizes that state-of-the-art research core facilities are central to the success of individual research operations and the overall research mission of the University. Flow cytometry remains the gold standard for high throughput analysis cells at the single cell level, a critical approach when evaluating heterogeneity in cellular microenvironments. Conventional flow cytometers however are limited by which fluorescent proteins they can detect and the number of concurrent proteins that can be evaluated simultaneously. Spectral flow cytometers are revolutionary in their ability to simultaneously detect and distinguish between fluorescent proteins previously deemed as incompatible with conventional flow cytometers. Drexel University is requesting funds in support of a BD Biosciences Symphony A5 Spectrally Enabled flow cytometer with 5 lasers, 48 fluorescence and 2 scatter channels, and a high-throughput sampler (HTS) system to support deep profiling of cellular heterogeneity in mouse and human samples. This flow cytometer will become the flagship cytometer of the newly created Flow Cytometry Core Facility at Drexel University, to be housed in the Departments of Microbiology and Immunology and Medicine at the College of Medicine and provide support to all flow cytometry users at Drexel University. This application is supported by Major and Minor Users from the Departments of Microbiology and Immunology, Pharmacology and Physiology, and Medicine in the College of Medicine; and the College of Biomedical Engineering, demonstrating the broad impact and need for high parameter flow cytometry.

NIH Research Projects · FY 2026 · 2024-09

The plasma-membrane monoamine transporters (MATs), including the serotonin (SERT), norepinephrine (NET) and dopamine (DAT) transporters, serve a pivotal role in limiting monoamine-mediated neurotransmission through the reuptake of their respective neurotransmitters. MATs are targets for the treatment of numerous neurological disorders such as depression, anxiety, and attention deficit hyperactivity disorder (ADHD), and they serve as target proteins for major drugs of abuse such as amphetamine and cocaine. The continuing need for therapeutic drugs to treat brain disorders involving aberrant monoamine signaling provides a compelling reason to further our understanding of transporter function and to identify novel ways of targeting them. This project builds on our recent discovery of an allosteric site (A2) within the MATs that can serve as a target site for modulating their activity. Previous experiments in our group targeted the allosteric A2 site in SERT and identified molecules that interact with this site and display remarkable transporter-modulating activities. These compounds have revealed that engaging this site modulate MAT activity in entirely novel ways, including affecting the interaction with transporter ligands such as the selective serotonin reuptake inhibitors (SSRIs) and psychostimulants. In corresponding experiments on DAT, we have identified compounds, KM822 and sydnocarb among others, that similarly modifies DAT function. We find that these compounds interfere with the interaction of DAT with exogenous ligands and attenuates psychostimulant-elicited behaviors in rodents. Computational simulations further support the premise that compounds interacting with the allosteric A2 site can allow transport while interfering with the interaction of the transporter with exogenous ligands like cocaine. The overarching hypothesis of this project is that the specific engagement of the allosteric site in DAT will provide valuable information regarding mechanisms of the dopamine transport process and could provide novel therapeutic avenues for developing DAT-based medications. We propose to pursue this idea by further characterizing the compounds to study allosteric modulation of DAT. We will in Aim 1 elucidate mechanisms of allosteric transporter modulation through computational modelling and molecular simulations coupled with functional and biochemical studies. In aim 2 we will evaluate the in vivo utility of the compounds by examining their effects on psychostimulant-elicited behaviors in rodents. Finally, in Aim 3, we will employ structure-based design to identify A2-specific compounds with improved properties. Consequently, the successful completion of this project will result in the development of novel ligands of DAT that can be employed as experimental tools to provide critical mechanistic information regarding allosteric transporter modulation. Furthermore, the design and development of novel allosteric modulators of DAT will enable a systematic evaluation of the beneficial potential of these compounds to ultimately provide new therapeutic opportunities.

NIH Research Projects · FY 2025 · 2024-09

MODIFIED PROJECT SUMMARY Childhood obesity prevalence keeps rising, especially among school-age children. Children of origins in Asia and the Pacific Islands (Asian/PI), as a whole, have lower obesity prevalence; but, at lower BMI levels, they have higher risk of obesity-related diseases relative to White peers. Asian/PI children have remained largely invisible in obesity prevention efforts, though obesity prevalence varies widely among Asian/PIs, the fastest growing demographic group. Data scarcity is a significant barrier to the design of strategies to prevent obesity for all children and reduce gaps in obesity risk. Nutrition policies—those that regulate the nutritional content of foods and beverages in schools, including the so-called “competitive” foods sold separately from school meals—could play a key role in the primary prevention of obesity and related chronic diseases. The community food environment near schools can also influence obesity (e.g., through children’s access, purchases and consumption of unhealthy foods). No studies have examined the combined influences of multiple nutrition policies and community food environments on child obesity and related heterogeneity among Asian/PI children. Using unprecedented, longitudinal BMI data on >1 million Asian/PI children, this quasi-experimental study evaluates policy and environmental effects on BMI. The first of its kind, this longitudinal study will: (1) determine the effects of federal and state nutrition policies designed to improve food and beverages in schools on obesity across eleven Asian/PI population groups; and (2) investigate how community food environments modify the effect nutrition policies on obesity. To obtain robust inferences, the study uses the best available methods to evaluate non-randomized exposures: interrupted time series design and “difference-in-difference” analysis to improve causal inferences. The study’s powerful design links longitudinal BMI measures with time-varying measures of the community food environments of all the public schools to which children attended. Expected results: This study will: (i) strengthen the evidence base by elucidating the causal effects of large scale nutrition interventions on obesity among Asian/PI populations; (ii) identify nutrition environments near schools where nutrition policies are most effective; and (iii) illuminate environments (inside and/or near schools) where additional interventions are needed. The study results have potential to inform strategies focused on two major public health goals—preventing child obesity and reducing obesity gaps across Asian/PI populations.

NIH Research Projects · FY 2025 · 2024-09

Project Summary Biologic drugs and nanomedicines with conjugated polyethylene glycol (PEG) show extended circulation in the blood, increasing therapeutic efficacy. The U.S. FDA has approved more than 30 PEGylated biologics, including proteins, nucleotides, and peptides, and a few PEGylated nanomedicines, for example COVID-19 mRNA vaccines. Attached PEG chains increase the hydrodynamic radiuses of these therapeutics to reduce their renal clearance during blood circulation. More importantly, PEG conceals therapeutics from immune cells by repelling plasma proteins, rendering therapeutics stealth behavior. The adsorption of a few types of plasma proteins onto therapeutics can lead to the removal of therapeutics by immune cells. PEG chains are hydrophilic and flexible. They can repel plasma proteins through a thermodynamic-driven entropic repulsion. Despite the unique advantage, the application of PEGylated therapeutics is limited by the presence of anti-PEG antibodies (aPEG Abs). These antibodies not only accelerate the clearance of PEGylated therapeutics and attenuate their efficacies but may also cause severe side effects. Varied percentages of populations were found to have pre- existing aPEG Abs in different studies, with the percentage as high as 40%. The high prevalence is likely due to the broad use of PEG in cosmetic and healthcare products. To further improve the pharmacokinetics of therapeutics and circumvent the problem of aPEG Abs, researchers have strived to find PEG alternatives. Among these alternative polymers, zwitterionic polymers have attracted the most attention. In contrast to PEG, zwitterionic polymers repel protein adsorption by forming a hydration layer around the polymers. We hypothesize that zwitterionic PEG (ZPEG) that combines the advantageous characteristics of both PEG and conventional zwitterionic polymers will be superior to them in extending the circulation of therapeutics and minimize the generation of anti-ZPEG antibodies. To develop a ZPEG to replace PEG for therapeutic delivery, we propose the following research plans: 1) synthesize and characterize ZPEG with different chemical structures and reveal the mechanism of enhanced blood circulation of ZPEG-modified proteins; 2) investigate the immunogenicity of ZPEG; 3) investigate the pharmacokinetics and immune responses of nanoparticles covered with ZPEG. Because of the broad application of PEG, an excellent PEG replacement will generate tremendous societal impact. This project will pave the way to replace PEG with ZPEG in therapeutic delivery for minimized side effects and consistent efficacy.

NIH Research Projects · FY 2025 · 2024-09

Drexel University proposes to establish a robust and innovative program, Drexel DREAM (health Disparities, Research, Experiential Learning, Research Skills and Aging Science, and Mentorship) Scholars Program, to enhance the training of the biomedical, behavioral, and clinical research workforce in aging research. This proposal, a collaboration across Drexel, is led by the College of Nursing and Health Professions and College of Medicine and leverages the expertise of nationally and internationally recognized faculty researchers across Drexel who are members of the Cell2Society Aging Research Network (Cell2Society), a Drexel Area of Research Excellence, and are committed to training the future workforce in aging research. The DREAM Scholars program is built upon 5 pillars: 1) health disparities which leverages the university’s areas of academic excellence and opportunities related to health innovation and health access and wellness; 2) faculty expertise in aging research approaches that span the continuum from the bench to policy in three key thematic areas: preventing and managing chronic conditions, enhancing active and purposeful living, and enabling aging in place; 3) experiential learning; 4) an innovative virtual learning community (VLC) where students obtain digital badges for mastering new knowledge in research skills and aging science; and 5) faculty mentorship for each DREAM Scholar throughout their undergraduate studies. The overall goal of the DREAM Scholars Program is to expose undergraduate students to research in aging that spans from the cell to society and in the long-term increase the biomedical workforce. We will recruit and train 22 undergraduate students who completed freshman year to participate in the DREAM Summer track- a noncredit full-time 10-week paid summer aging research training program and 38 undergraduate students in their sophomore, pre-junior, or junior year, to participate in the DREAM CO-OP Scholar Track- a noncredit full-time 26-week paid aging research training program as their cooperative education rotation. DREAM Scholars will be paired with a Cell2Society faculty mentor to conduct research, participate in a VLC where they will learn research skills and aging science, recognize health disparities in aging, be mentored to enhance professional and personal growth, and receive digital badges upon completion of activities related to reframing aging, responsible conduct of research, aging science, research skills, and health disparities. The specific aims are 1) evaluate the effectiveness of the DREAM Scholars program in shaping career goals with an awareness of aging research, 2) evaluate the effectiveness of the DREAM Scholars program in developing research skills for undergraduate students, 3) foster an awareness of health disparities in aging research, and 4) evaluate the DREAM Scholar program implementation processes.

NSF Awards · FY 2024 · 2024-09

By the time they enter middle school, many youth have opted out of engineering pathways due to limited exposure to engineering fields and a lack of encouragement or support. This project will address this issue by developing and testing a promising model of informal engineering programming designed to foster engineering identities among youth aged 9-12. This model will iterate on the existing work of St. Elmo Brady STEM Academy, a longstanding program which has provided engineering experiences to youth from Houston. This project will offer a no-cost, 16-week after-school informal engineering program--which includes features such as hands-on engineering design projects, opportunities to interact with professional engineers and scientists, family engagement Saturday sessions, community partnerships, engineering fairs, and support from mentors who are first-generation college undergraduates in engineering--to hundreds of youth in Houston. Research will explore how aspects of this informal engineering environment supported the engineering identity development of the participating youth. The model of informal engineering programming, and associated pedagogical materials, will be shared widely via professional networks of informal educators and engineering educators. Ultimately, this project is likely to promote engineering pathways and careers by illustrating how familial support, social supports such as mentors and community involvement, and engineering experiences can encourage all youth to see themselves in engineering. The University of Houston and Drexel University will use mixed-method research to investigate whether and how a model of informal engineering programming fosters engineering identity among participating youth. To achieve this purpose, the research team will analyze the following types of data: video-recordings of youth as they participate in the 16-week program; transcriptions of focus groups with the youth; and a pre-and post-administration of the Engineering Identity Development Scale. A subset of youth participants will engage in Photovoice in which they photograph, caption, and discuss elements of their experiences related to the program. This data source, in addition to other youth artifacts and transcripts from focus groups, will be used to ascertain whether and how particular programmatic elements foster the development of engineering practices and habits of mind among participating youth. Finally, the research team will conduct focus groups with undergraduate mentors and family members. They will analyze transcripts from these focus groups, as well as observational data, to investigate how mentors and families implement practices that foster youths' engineering identities, and how engineering programs can be designed to better support family engagement. The empirical findings from these analyses will be disseminated widely via professional networks and publications. This project will result in a field-tested, empirically-based model of informal engineering programming that fosters engineering identity and encourages all youth to consider and pursue engineering pathways leading to engineering careers. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Following spinal cord injury (SCI) at or above thoracic level 6 (T6), descending supraspinal control over the spinal neurons associated with sympathetic function is severed. This, along with plasticity within these neurons themselves, results in exaggerated sympathetic reflexes known as sympathetic hyperreflexia. This increase in sympathetic activity following SCI causes severe dysfunction of organs receiving sympathetic input, such as the spleen and vasculature. This contributes to cardiovascular disease and immune dysfunction, two leading causes of morbidity and mortality in the SCI population. Therefore, increasing understanding of the mechanisms underlying this plasticity may identify a possible therapeutic for sympathetic hyperreflexia that would enormously benefit SCI individuals. SCI-induced reduction of receptor cation-chloride cotransporter type 2 (KCC2) in neuronal membranes disrupts chloride homeostasis to decrease synaptic inhibition and has been implicated in heightened spinal motor reflexes after SCI. Whether KCC2 contributes to sympathetic hyperreflexia after SCI is not known. We theorize that SCI results in loss of KCC2 in the membrane of spinal neurons associated with sympathetic function to contribute to sympathetic hyperreflexia. We also postulate that the loss of KCC2 in the neuronal membrane results from activation of NF-B, a transcription factor that is downstream of multiple pro-inflammatory cytokines known to be increased following SCI. This proposal will focus on the hypothesis that hyperexcitability of spinal, sympathetically-associated neurons after SCI is due to downregulation of KCC2 expression via increased NF-B activation. The primary goals of this proposal are to: 1) investigate KCC2 in the development of sympathetic hyperreflexia following SCI and if enhancing KCC2 function mitigates sympathetic hyperreflexia (Aim 1); 2) determine if SCI-induced KCC2 downregulation occurs via NF-B (Aim 2).

NSF Awards · FY 2024 · 2024-09

The noble-liquid bubble chamber is a newly developed technology with a unique combination of high sensitivity to particle interactions with atomic nuclei, but extremely low sensitivity to interactions with atomic electrons. The Scintillating Bubble Chamber (SBC) Collaboration will develop this technique and use it in the study of dark matter and neutrinos. While astrophysical observations indicate that most of the matter in the universe is so-called ‘dark matter’, very little is known about the nature of dark matter. The SBC technique is complementary to many other experimental efforts also seeking to directly observe dark matter and would be an especially powerful experimental tool if it turns out that dark matter consists of particles of similar mass to protons – which make up most of the ‘normal matter’ in the universe. This project involves operation support, data analysis and calibration by graduate and undergraduate students at Drexel University of SBC noble-liquid bubble chambers for the low-background detection of sub-keV nuclear recoils. As a neutrino experiment, SBC’s unique capabilities enable the study of elastic scattering of neutrinos off atomic nuclei to reveal new insights. If successfully developed, this technology will enable searches for GeV-scale dark matter particles to the solar neutrino floor, and precision measurements of neutrino properties via coherent elastic scattering (CEvNS) of reactor neutrinos. The SBC Collaboration is commissioning a 10-kg liquid argon bubble chamber at Fermilab to calibrate the low-threshold reach of this technology. The unique sensitivity to sub-keV nuclear recoils motivates a novel in-situ calibration approach combining photoneutron sources to induce keV-scale nuclear recoils and an entirely new calibration technique employing elastic scattering of gamma rays to induce sub-keV nuclear recoils. Monte Carlo simulations and data analysis tools developed with this project will be used to interpret the response of the detector to the calibration sources and develop a precision data-driven response model to dark matter particles and neutrinos, enabling the physics goals of the SBC experimental program. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2024 · 2024-09

Despite the significant efforts devoted to solid-state battery research and the impressive performance improvement accomplished during the past two decades, a fundamental understanding of metal nucleation, growth, and interaction with solid electrolytes remains elusive. This research aims to bridge this knowledge gap by establishing a new electrolyte system to systematically decouple complex factors such as local mechanical, chemical, and electrochemical effects on lithium and sodium electrodeposition. The novel patterned solid polymer electrolytes (pSPEs) are designed to have micro-size features that can be used to understand the battery charging and discharging processes. This class of unique pSPEs is anticipated to allow for a detailed mechanistic study of metal nucleation and growth at the electrode/electrolyte interface. Thus, the research addresses a grand challenge facing the energy research community, and if successful, will lead to a new type of solid-state battery. The educational component of the project includes (1) developing class modules that will be used in graduate courses, (2) mentoring graduate and undergraduate students, and (3) involving high school students and teachers in the project’s research activities. This project aims to fabricate a series of spatially heterogeneous solid polymer electrolytes for solid-state batteries. The patterned solid polymer electrolytes (pSPEs), fabricated using soft lithography, will possess spatially controlled heterogeneity at the metal anode-electrolyte interface, which allows for systematically decoupling the convoluted local mechanical, chemical, and electrochemical effects on lithium (Li) and sodium (Na) electrodeposition in solid-state batteries. The specific aims are (1) fabricating pSPEs with controlled spatial heterogeneity in various properties using soft lithography; (2) understanding the nucleation mechanism of lithium and sodium metal at the electrode-pSPEs interface; (3) understanding the growth mechanism of lithium and sodium metal at the electrode-pSPEs interface. A library of pSPEs will be fabricated with controlled spatial heterogeneity varied from µm to >100 µm, selected based on the typical nucleation density of Li and Na. The pSPEs will serve as a new materials platform to investigate metal electrodeposition, and they will significantly improve fundamental understanding of the complex electrode/electrolyte interface in solid-state batteries. The knowledge gained from this project will benefit the next generation of battery design and pave the way for safer and more efficient energy storage solutions. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2024-09

Substance use disorders (SUD) continue to be a major public health concern globally, worsening the health of millions of people and costing hundreds of billions of dollars each year. The use of addictive substances is a major risk factor for CNS dysfunction, and also increases risky behaviors, exposing individuals with SUD to viral infections such as HIV. People with HIV (PWH) have a disproportionately high level of substance misuse, in whom these substances accelerate and exacerbate the development of disease, particularly increasing the risk for developing neurological complications (neuroHIV). Importantly, neuroHIV remains prevalent even with antiretroviral therapy (ARV), making the treatment of neurological complications a high priority in the current era. NeuroHIV is driven by CNS myeloid cells such as macrophages which promote neuroinflammation and are primary targets for infection in the brain, also potentially serving as viral reservoirs. All addictive substances increase extracellular dopamine in the CNS, exposing CNS macrophages to aberrantly high levels of dopamine. Our lab has shown that dopamine promotes inflammation in human macrophages and increases HIV entry into these cells. However, it remains unclear how dopamine signals in these immune cells to drive inflammation and how these signaling pathways are exacerbated in the presence of HIV. Dopamine canonically signals through its cognate GPCR (D1, D2, D3, D4, D5) to regulate cAMP signaling, but in immune cells, our published data show dopamine does not activate this pathway. Instead, our data show that dopamine signals by increasing Ca2+ flux and PKC phosphorylation, and our preliminary studies indicate dopamine can also act on adrenergic receptors to activate Akt. This underlies the focus of this proposal, which examines the capacity of these alternative signaling pathways to regulate dopaminergic immunomodulation. Specifically, we hypothesize that dopamine drives macrophage inflammation through D1 dopamine receptors by acting through alternative signaling pathways and that these mechanisms are exacerbated in the presence of HIV. We will test this hypothesis using a multifaceted approach employing high content imaging and analysis to identify the specific pathways mediating dopaminergic immunomodulation in macrophages in the presence or absence of HIV. We will use in vitro pharmacological inhibition and molecular knockdown of catecholamine receptors (dopamine and adrenergic receptors) in both infected and uninfected macrophage models to examine the receptors (Aim 1) and downstream intermediates (Aim 2) that mediate the effects of dopamine on inflammation. We will use the activity of NF-kB and production of inflammatory cytokines as readouts, examining both primary human monocyte derived macrophages and pluripotent stem cell derived macrophages. These studies will significantly advance our understanding of the cellular mechanisms underlying the role of dopamine and addictive substances in HIV neuropathogenesis.

NSF Awards · FY 2024 · 2024-08

NON-TECHNICAL DESCRIPTION: Energy storage devices, such as batteries, are essential for achieving clean energy and a sustainable future. Lithium-ion batteries (LIBs), which are widely used in portable electronics, electric vehicles, and grid-scale energy storage, present safety issues related to fire hazard and raise concerns due to the limited abundance of lithium. Aqueous zinc-ion batteries (AZIBs) offer an attractive alternative to LIBs because of their high performance characteristics, low cost, environmental friendliness, and safety. However, the widespread adoption of AZIB technology is hindered by the need to develop cathode materials that can efficiently insert and extract zinc ions while remaining stable over many battery discharge/charge cycles. This project, supported by the Ceramics program in the Division of Materials Research at NSF, explores strategies to improve the cycling stability of layered vanadium oxide cathodes in AZIBs for both slow and fast battery operations. These strategies include the incorporation of stabilizing cations in the interlayer region of the vanadium oxide structure, the partial replacement of vanadium with another transition metal in the layer structure, and the formation of a tight oxide/carbon contact on the surface or within the volume of the synthesized particles. These approaches are enabled by the use of MXenes - transition metal carbide nanoflakes - as precursors in a synthesis method called chemical preintercalation, developed by the PI. This interdisciplinary project engages and educates students with diverse backgrounds by offering research opportunities in electrochemical energy storage at undergraduate and graduate levels. It also integrates topics on ceramic material transformations, energy storage, and in situ electrochemical characterization into the engineering curriculum through courses taught by the PI. Additionally, this project enriches outreach programs by creating an activity based on coloring outline images prepared from real microscopy images of synthesized materials. The PI also teaches students how to digitally color microscopy images to create artistic illustrations and organizes a competition featuring these images at her home institution. TECHNICAL SUMMARY: This project, supported by the Ceramics program in the Division of Materials Research at NSF, aims to mitigate performance degradation of chemically preintercalated bilayered vanadium oxide (BVO) cathodes in aqueous zin-ion batteries (AZIBs) caused by limited ion diffusion, low electrical conductivity, dissolution in the electrolyte, and formation of unwanted by-products during cycling. The goal of this project is to develop new ceramic materials with tunable structures that exhibit high zinc ion storage capability, rapid electron and ion transport, and enhanced electrochemical stability. The goal is achieved by testing the hypothesis that high capacity, long cycle life and fast charging can be delivered by MXene-derived (MD) vanadium oxide electrodes in AZIBs. This is pursued through chemically preintercalated ions (CPI), doping at vanadium sites, and controllable heterointerfaces. Using MXene nanoflakes as precursors allows for unique morphologies, structures and chemical compositions, leading to enhanced zinc ion diffusion, increased electrical conductivity, and suppressed electrode dissolution. The research addresses three objectives to overcome limitations of layered vanadium oxide cathodes in AZIBs: (1) Enhance Zn2+-ion diffusion by controlling interlayer spacing via chemical preintercalation of ions, using MXene nanoflakes for unique 2D morphology and improved electrochemical stability; (2) Suppress V–O cathode dissolution by doping vanadium sites in the BVO structure with another transition metal, achieved using solid-solution MXenes; (3) Further advance electrochemical stability and rate capability through the formation of oxide/carbon heterointerfaces and/or conductive carbon surface-protection layers by tuning MXene monolayer thickness. The mechanism of electrochemical stabilization at various cycling rates is established via a comprehensive suite of in-situ electrochemical characterization approaches, including XRD, SEM and pH measurements. The insights into ion diffusion coefficients, charge storage mechanism and evolution of electrodes during electrochemical cycling, obtained in this project, enable the design of cathode materials with enhanced energy/power storage capabilities and electrochemical stability in AZIBs. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2024-08

Millions of adults in the U.S. with overweight or obesity would like to improve their health and quality of life via weight loss, yet utilization of evidence-based weight loss interventions is low. Instead, adults commonly attempt self-guided weight loss, which has poor efficacy. When adults do use evidence-based interventions (which include behavioral, dietary, commercial, surgical, and pharmacological options), long-term engagement is suboptimal, as some individuals select interventions that are poorly matched to their needs. The proposed project is designed to test the use of patient navigators to increase uptake of and persistence with evidence-based weight loss interventions. Navigators have been successfully used in other areas of healthcare to facilitate engagement with various treatment and prevention services. However, no data are available on the feasibility, acceptability, or efficacy of a weight loss navigator program in adults. In the proposed study, the weight loss navigator will assess treatment barriers and preferences, provide education about evidence-based options, support decision making, and address ambivalence about change. The navigator will not directly provide weight loss intervention; rather, the navigator’s role will be to assist participants in utilizing existing evidence-based interventions for weight loss from other sources. Navigators will maintain long-term relationships with participants to monitor adherence and acceptability of the selected intervention and, as needed, revisit other intervention options. Participants (N = 68 adults with a BMI >27 kg/m2 who are interested in weight loss) will be randomly assigned for a 12-month period to either usual care or the navigator condition. In the navigator condition, participants will attend individual sessions (delivered remotely) and receive personalized text messages. Assessments will be conducted at months 0, 6, and 12, with the primary outcome, weight loss, being assessed remotely with wireless scales. The proposed research project is highly responsive to NIDDK’s new “Small R01” funding opportunity, which supports pilot clinical trials that acquire preliminary data regarding the effects of an intervention. Specifically, this project will 1) demonstrate the feasibility and acceptability of various aspects of the project, 2) calculate effect sizes for weight loss and utilization of evidence-based interventions, and 3) collect qualitative feedback from navigators and participants to inform improvements in the navigator program for future research. This innovative project will provide much needed data about the promise of navigators in meeting the needs of adults with overweight and obesity. It is expected that if benchmarks for this study are met, funding will be sought for a fully powered clinical trial that examines efficacy, cost, mediators, and moderators. This line of research has the potential for a large impact on clinical practice and public health by enhancing the utilization of evidence-based weight loss interventions.

NSF Awards · FY 2024 · 2024-08

Networks of various kinds and scales arise across biological, social, and physical systems. Moreover, self-similarity manifests in real-world networks in multiple ways, from the hierarchical self-similarity of the Internet, to the fractal-like structure of dendritic trees of neurons and protein interaction networks, and to the multiscale organization of social and epidemiological networks. Mathematical modeling helps to understand the principles underlying network dynamics, which can be used for effective prediction and control of real-world networks. This research studies the implications of self-similar structure of networks on their emergent dynamics. It aims to bridge analytical theories of fractals and differential equations on fractals with applications in network science. A combination of techniques from the analysis on fractals and dynamical systems will be used to develop new tools for the analysis, prediction, and control of self-similar network dynamics. Graduate and undergraduate students will be trained and contribute to these research activities. The principal investigators will develop a set of model problems aimed at elucidating dynamics of self-similar networks. They will consider the Kuramoto model of coupled phase oscillators on graphs approximating the Sierpinski Gasket and other fractals and analyze them using a combination of analytical and numerical techniques. The goal of the first project is to develop a geometric approach to the construction of harmonic maps from post-critically finite fractals to a circle. The outcomes of this project will be used to construct stable steady states of coupled oscillator models on graphs approximating these fractals. The second project is focused on synchronization and bifurcations in self-similar networks. The third project studies epidemiological networks based on an SIR (Susceptible-Infected-Removed) model on graphs approximating fractals. Combined these projects are expected to deliver a new set of tools for studying interacting dynamical systems on self-similar sets. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2024-08

PROJECT ABSTRACT The proposed study will conduct a detailed examination of the impact of ableism on women with intellectual and developmental disabilities (I/DD) during pregnancy and the postpartum period, and will compare outcomes experienced by this group and their infants to those of peers without I/DD. Despite the growing number of individuals with I/DD giving birth and the substantial health needs and comorbidities present in this population, very little is known about the impact of ableism on healthcare access and service use among women with I/DD in the periods before and after delivery. Examining the healthcare experiences of these women in the Medicaid system in the US is a critical starting point. Medicaid funds almost half of births in the US and is among the only healthcare coverage options available to birthing people with disabilities including I/DD, most of whom do not have access to employer-sponsored health insurance. In addition, the Medicaid beneficiary population is diverse and includes birthing people from higher maternal risk groups, including Black women and women from other racial/ethnic minority groups who are disproportionately impacted by mental health diagnoses and maternal morbidity and mortality. We propose to use the latest available national Medicaid claims data (2016- 2023) to identify women with I/DD between 14 and 50 years of age who have given birth and are at risk for experiencing ableism and link them to their infants, who are also typically enrolled in Medicaid. We will compare pregnancy, childbirth, and postpartum health outcomes among women with I/DD compared to women without I/DD. By linking these women to their infants, we will assess the impact of ableism on neonatal and post-natal health outcomes, morbidity, and mortality. We will also link Medicaid information to other key data sources, including Census-based indicators of community-level social determinants of health and state Medicaid policy data to identify structural ableism and opportunities for systemic intervention. Using Medicaid- generated data that identifies service providers and designing data collection instruments aimed at assessing ableism, we will then survey and interview obstetric service providers to identify how attitudinal ableism impacts barriers and facilitators to service delivery and potentially modifiable components of healthcare access, referral, and service delivery (e.g., training, preparedness, communication) that may moderate the relationship between I/DD status and outcomes during pregnancy and postpartum. The information generated by this study is essential to identifying opportunities to address attitudinal and structural ableism to improve the system of care to meet the needs of the growing group of birthing women with I/DD and support outcomes for their infants. Completion of this study will result in the most substantive national work to date to identify modifiable policy, system, and provider factors to mitigate the impact of ableism and support improved outcomes for women with I/DD during the pregnancy and postpartum periods and their babies, with the goal of reducing observed adverse pregnancy and postpartum outcomes among women from underserved groups.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY HIV infection results in abnormal menstruation and alterations in circulating hormones. HIV infection is also highly comorbid with drug use. Women who use drugs are at an elevated risk of HIV infection and show accelerated HIV progression. In rodents, estrous cyclicity and cocaine-related behaviors are both regulated by the medial preoptic area (mPOA) of the hypothalamus. The mPOA regulates gonadal hormone release which feeds back onto the mPOA to regulate its activity. The mPOA regulates cocaine-related behaviors through primarily GABAergic projections to the ventral tegmental area (VTA), which modulates dopamine release in the nucleus accumbens (NAc). Lesion of the mPOA disrupts estrous cycling and enhances cocaine-induced locomotion. These mPOA lesion-induced changes are associated with increased cFos expression and dopamine release in the NAc, together implicating mPOA in both estrous cyclicity and cocaine-related behavior. Our preliminary data in the EcoHIV mouse model of HIV infection indicate disruptions in estrous cycle following inoculation with EcoHIV. Further, EcoHIV infection enhanced cocaine-induced locomotor sensitization, a model of cocaine- related behavioral plasticity, and increased cocaine-induced cFos expression in the NAc. Thus, the mPOA may represent a common site of dysregulation following EcoHIV infection, leading to alterations in both estrous cycle and cocaine-related behavior. Consistent with this, we have observed that EcoHIV-infected female mice exhibit attenuated cFos expression in the mPOA. This R21 proposal will test the overarching hypothesis that EcoHIV infection dysregulates the mPOA estradiol system, leading to enhanced cocaine-induced locomotor sensitization. Aim 1 will determine the effects of EcoHIV inoculation and cocaine exposure on estradiol levels and receptor expression in the mPOA. Aim 2 will determine the effects of EcoHIV inoculation on engagement of mPOA→VTA and VTA→NAc projections in cocaine-induced locomotor sensitization. Aim 3 will determine the effect of chemogenetic activation of mPOA→VTA projections on cocaine-induced locomotor sensitization following EcoHIV infection. It will also determine the effect of an estrogen receptor α antagonist on cocaine- induced locomotor sensitization following EcoHIV infection. The results of these experiments will identify a mechanism by which EcoHIV infection alters behavioral response to cocaine and the contribution of the mPOA→VTA→NAc pathway to cocaine-related behavior following EcoHIV infection. Further, we will gain significant knowledge of sex differences in the regulation of cocaine-related behavior by the hypothalamus.

NIH Research Projects · FY 2024 · 2024-08

Project Summary Conformational variations in α-syn fibrils are proposed to be implicated in the emergence of distinct diseases within synucleinopathies, including Lewy body dementia (LBD), Parkinsons’s disease (PD), and multiple system atrophy (MSA), suggesting a molecular fingerprint closely connected to clinical diagnosis. However, the mechanisms underlying the appearance of these disease-specific conformations and their impact on the progression of distinct pathologies in synucleinopathies remain largely unclear. Motivated by the existing knowledge gap between structural polymorphism and disease entities, the goal of this proposed research is to investigate how α-syn pathology propagates in a disease-specific manner, by focusing on the molecular interactions between α-syn fibril structures and diverse cellular environments. To achieve this, we will employ a multidisciplinary approach based on the combination of biophysical approach, molecular biology, and human organ-on-a-chip technology. Building upon our complementary expertise in neurodegenerative amyloid fibril research and human organ-chip development, we will produce various forms of α-syn fibril seeds, characterize their conformations, and investigate their functions in human vascularized brain-on-chips with an unprecedented physiological realism. The central hypothesis posits that the membrane-mediated polymorphisms of α-syn fibrils are a key factor in the emergence of the distinctive pathological features of synucleinopathies, including LBD and PD, through the molecular interactions between α-syn fibrils and cellular membranes. These interactions are significantly influenced by the distinct conformations of α-syn fibrils and the varying membrane conditions found in different types of brain cells. This hypothesis will be tested by pursuing three specific aims: 1) Generate the polymorphic α-syn fibrils in the presence of various physiologically relevant membranes and characterize their functional properties; 2) Create microengineered 3D culture arrays for on-chip production of vascularized human mid-brain tissues and validate the propagation of α-syn pathology; and 3) Explore the cell-type specific pathological impacts of lipid-associated polymorphic α-syn fibrils and compare the molecular structures and interactions of these polymorphic α-syn fibrils. The expected outcomes will provide novel insights into the molecular mechanisms underlying conformation-dependent neuropathology. Consequently, these findings will contribute to the design and development of small molecules aimed at either inhibiting aggregations or detecting neurotoxic aggregates. Additionally, the brain-on-a-chip established in this study has the potential to serve as a promising drug screening platform capable of faithfully replicating cellular responses to pharmaceutical agents. Ultimately, this study will aid in the development of advanced diagnostic and therapeutic approaches aimed at synucleinopathies, thereby mitigating the adverse impacts of neurodegenerative disorders on public health and societal functioning.

NIH Research Projects · FY 2025 · 2024-08

The heavy burden of Plasmodium falciparum and Plasmodium vivax malaria drove international efforts to coordinate and integrate tools and programs for mosquito vector control, rapid diagnosis, and drug treatment. Success has been significant but may be approaching a limiting boundary. The effort to develop a vaccine to further enhance malaria control has faced many challenges. The advancement of the pre-erythrocytic-stage RTS,S vaccine is a major accomplishment, providing the foundation for an effort that must continue to improve efficacy and durability of vaccine-induced protection to further reduce the disease burden. In this regard, the development of a multivalent vaccine that concurrently targets pre-erythrocytic-stage, blood-stage and sexual stage parasites is attractive but adds complexity. The immunogenicity of each component must be maintained while effectively driving both antibody and cell-mediated immune responses. We have utilized a recombinant antigen plus adjuvant approach to systematically formulate an immunogenic, multi-stage, multivalent malaria vaccine made feasible through the use of an optimized malaria-specific carrier protein, P. falciparum merozoite surface protein 8. While successful, there are still challenges and limits to this approach considering the breadth and nature of immune responses that are needed. Several features of the emerging mRNA vaccine technology are extremely attractive for malaria vaccine development and may overcome challenges inherent to producing multiantigen, multistage formulations. At the same time, the technology must be evaluated and optimized to address issues unique to Plasmodium and malaria. In the proposed studies, we will test the hypothesis that an mRNA-based vaccine can be optimized to concurrently drive durable, antibody-mediated and cell-mediated protective immune responses to pre-erythrocytic and blood-stage malaria vaccine candidates. We will optimize mRNA vaccine-induced, antibody-mediated, and cell-mediated protection to pre-erythrocytic stage parasites using a novel P. falciparum circumsporozoite protein (PfCSP) vaccine candidate. We will design, produce, and evaluate an mRNA-based vaccine targeting P. falciparum reticulocyte-binding protein homologue 5 (PfRh5) to drive high titer antibodies that block merozoite invasion of erythrocytes. We will apply data on a highly protective, Plasmodium yoelii mRNA blood-stage vaccine to the design and testing of a vaccine targeting the 19 kDa C- terminal domain of P. falciparum merozoite surface protein 1 (PfMSP119). We will evaluate a multivalent mRNA- based vaccine that concurrently targets sporozoites and liver-stage parasites (PfCSP) as well as blood-stage merozoites (PfRh5 and PfMSP119). Success in the effort will determine the potential and the limitations of mRNA- based technology for delivery of a multicomponent malaria vaccine and provide a foundation to integrate additional targets and/or modifications to advance development of a true multi-stage malaria vaccine.